PBMTC Abatacept

Principal Investigator: Andrew Harris
Keywords: Abatacept , Calcineurin , Mthotrexate Department: Pediatric Hematology/Oncology
IRB Number: 00063011 Co Investigator:  
Specialty: Hematology/BMT
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

SAMUEL  SORENSON
samuel.sorenson@hsc.utah.edu
8015877484

Brief Summary

This trial is being conducted as a step toward testing the long-term hypothesis that the costimulation blockade agent abatacept can be added to a standard acute graft-versus-host disease (aGvHD) prophylaxis regimen (which includes a calcineurin inhibitor (CNI) and methotrexate), to improve disease-free survival after unrelated donor (URD) hematopoietic stem cell transplantation (HSCT) for patients with hematologic malignancies. As a phase II study, the overall aim of this trial is to make a preliminary assessment of abatacept’s clinical safety and efficacy using short-term outcomes.  Thus, this trial is designed to test two hypotheses:

  1. A primary hypothesis that the addition of abatacept to calcineurin inhibition + methotrexate can decrease the incidence of early-onset (before day 100 post-transplant) Gr III-IV aGVHD in HLA 8/8 matched-unrelated donor transplants and Gr III-IV aGVHD in HLA 7/8 mismatched-unrelated donor transplants.
  2. A secondary hypothesis that its addition will not hinder post-transplant reconstitution of protective immunity against latent viruses.

To test these two hypotheses, this study will have the following Specific Aims.

Specific Aim #1:  To conduct a multicenter Phase II trial to assess the impact of abatacept on the incidence of aGVHD and its biology. We will compare investigational GVHD prophylaxis, abatacept combined with a CNI and methotrexate, to standard GVHD prophylaxis, a CNI and methotrexate alone in two patient strata.

Patients receiving an 8/8 HLA matched URD HSCT (stratum 1) will be randomly assigned to the investigational regimen or the standard regimen; all patients receiving 7/8 matched URD HSCT (stratum 2) will be assigned to the investigational regimen and be compared to a historical 7/8 matched URD control group drawn from the Center for International Blood and Marrow Research (CIBMTR) registry.

In both strata, correlative immunology studies will be performed to elucidate abatacept’s effects on the graft-versus-host response.

Specific Aim #2:  To assess the impact of abatacept on post-transplant reconstitution of protective immunity against viruses. This will involve monitoring the longitudinal recovery of lymphocyte subsets and virus-specific immunity, using tetramer analysis and viral stimulation assays. It will also involve monitoring viral infection and disease.

Inclusion Criteria

  1. Must be at least 6 years old and weigh 20 kg.
  2. Must have a willing unrelated adult donor (bone marrow or peripheral blood). Donors may have a single mismatch (i.e. be a 7/8) and this mismatch may be at the allele or antigen level; however, donors with allele level disparity should be given preference over those with antigen level disparity. The use of mismatched donors in which disparity is only in the host versus graft direction (because of recipient homozygosity) is discouraged because of the potentially heightened risk for graft rejection. Centers may perform extended typing (e.g. DQB1 and DPB1) according to institutional practices and use these results in selecting donors; however, it is recommended that this extending typing be used only to select between donors who are equally well matched with the recipient at the A, B, C and DRB1.
  3. All patients and/or their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
  4. Must have a high risk hematologic malignancy as defined below:
    1. Acute myeloid leukemia (AML).

     i.  Patients with AML in the first complete remission (CR) with intermediate or high risk cytogenetics according to SWOG/ECOG (or alternatively MRC) criteria for adults, and COG criteria for pediatric patients

ii. Patients with AML in First CR with high-risk disease as defined by one of the following abnormalities. CR is defined as an M1 marrow (<5% blasts by morphology), no evidence of extramedullary disease, and an absolute neutrophil count ≥ 1.0 x 109/L. Cases where the ANC is < 1.0 x 109/L and rising will also be considered. The PI will need to approve such cases for enrollment. Complete remissions without platelet recovery (CRp) will be considered complete remissions.

Indicators of High-risk Disease are as follows:

  1.      Flt3/ITD+ disease (if quantitative testing was performed, the allelic ratio must be > 0.4)
  2. Residual marrow disease (≥0.1% by flow cytometry) detected by multidimensional flow cytometry after completing at least one cycle of induction chemotherapy.
  3.       Secondary AML.  If the AML is secondary to treatment for another malignancy, the first malignancy must be in a complete remission.

4. High-Risk Cytogenetic abnormalities: Different intermediate and high-risk cytogenetic criteria have been defined for adult and pediatric AML. We will, therefore, use two sets of cytogenetic criteria, one based on Children’s Oncology Group (COG) criteria for pediatric patients and one based on Southwestern Oncology Group (SWOG)/Eastern Oncology Group (ECOG) or MRC criteria for adult patients.

Examples of high-risk cytogenetics:

  1. Adult patients (≥21 years):
    1.  -5/del (5q)
    2.  -7/del (7q)
    3.  inv 3q
    4.  del (9q)
    5.  abn 11q
    6.  abn 20q
    7.  abn 21q
    8.  abn 17P
    9.  t(6;9)
    10. t(9;22)
    11. complex karyotypes (≥ 3 unrelated abnormalities)

 

  1. Pediatric patients (<21 years)
    1. -5/del (5q)
    2.  -7

5. Other abnormalities associated with a higher risk for AML relapse. There are an increasing number of abnormalities being identified that have been associated with an intermediate or high risk of relapse, but have yet to be incorporated into cooperative group risk classification systems. Patients with AML characterized by these abnormalities will be considered. The PI will need to approve such cases for enrollment

(ii) Patients with a partial first remission (PR, defined as an M2 marrow (5-19% blasts by morphology), no evidence of extramedullary disease, and an absolute neutrophil count ≥ 1.0 x 109/L. Cases where the ANC is < 1.0 x 109/L and rising will also be considered. The PI will need to approve such cases for enrollment.

(ii) Patients in 2nd or greater complete or partial remission.

 

  1. Myelodysplastic syndrome
    1. Adult patients (≥21 years) with secondary disease or de novo disease that meet meet criteria for intermediate, high or very high-risk disease based on the Revised International Prognostic Scoring System.  Intermediate risk (3.1-4.5 points), high risk (4.6 - 6 points), very high risk (greater than 6 points).

(ii) Pediatric patients with MDS, regardless of subtype, will be eligible.

 

(c) Acute lymphoblastic leukemia (ALL).

  1. Given the poor prognosis of adults (≥21 years) with ALL, adults in 1st or greater complete remission will be eligible. CR is defined as an M1 marrow (<5% blasts), no evidence of extramedullary disease, and an absolute neutrophil count ≥ 1.0 x 109/L. Cases where the ANC is < 1.0 x 109/L and rising will also be considered. The PI will need to approve such cases for enrollment.Complete remissions without platelet recovery (CRp) will be considered remissions
  2. Given the generally good prognosis of children (<21 years) with ALL, they will have to meet one of the criteria listed below.  Additionally, children who are enrolled on a COG ALL trial for newly diagnosed or relapsed disease will have to meet the criteria for BMT outlined in that trial. CR is defined as an M1 marrow (<5% blasts), no evidence of extramedullary disease, and an absolute neutrophil count (ANC) ≥ 1.0 x 109/L. Cases where the ANC is < 1.0 x 109/L and rising will also be considered. The PI will need to approve such cases for enrollment. Complete remissions without platelet recovery (CRp) will be considered remissions.

 

  1. In 1st complete remission with a very high risk for relapse.
    1. Hyplodiploidy (<44 chromosomes)

       

      as evidenced by the results of routine analysis of G-banded chromosomes, DNA index (<0.81), or other appropriate methodology).)

    2. >1% residual marrow blasts by flow cytometry at the end of induction.
    3. >0.01% residual marrow blasts by flow cytometry at the end of consolidation.
    4. Early T-Cell Precursor (ETP) phenotype
  2. In 2nd complete remission with B-lineage disease after a marrow relapse occurring less than 36 months from diagnosis.
  3. In 2nd complete remission with T-lineage disease or Ph+ disease after a marrow relapse occurring at any time.
  4. In a 2nd complete remission with T-lineage disease after an extra-medullary relapse occurring less than 18 months from diagnosis.
  5. In 3rd or greater complete remission after a marrow or extramedullary relapse

6. Other indications for transplant in pediatric patients with ALL must be approved by the Study PI with a note to file reflecting study team discussion and approval.

(d) Patients with acute undifferentiated, biphenotypic, or bilineal leukemia, which is in 1st or greater complete remission (CR) or partial remission (PR).  Cr will be defined as an M1 marrow (<5% blasts), no evidence of extramedullary disease, and an absolute neutrophil count ≥ 1.0 x 109/L. Cases where the ANC is < 1.0 x 109/L and rising will also be considered. The PI will need to approve such cases for enrollment. CR without platelet recovery (CRp) will be considered complete remissions.) PR will be defined as an M2 marrow (5-19% blasts), no evidence of extramedullary disease, and an absolute neutrophil count ≥ 1.0 x 109/L.). Cases where the ANC is < 1.0 x 109/L and rising will also be considered. The PI will need to approve such cases for enrollment.

 

                           (e) Chronic myelogenous leukemia (CML).

 (i) Chronic phase with resistance to tyrosine kinase inhibitors.

(ii) accelerated phase (development of cytogenetic abnormality in addition to t(9:22), blood blast percentage ≥10, blood basophil percentage ≥20, platelet count <100,000 X 109/L)

  1.  blast crisis.
  2. 2nd or greater chronic phase.

 

  1. Acute Lymphoblastic Lymphoma in 2nd or greater complete remission.

Complete remission includes confirmed complete response (CR) defined as the disappearance of all evidence of disease from all sites for at least 4 weeks. Bone marrow and CSF must be normal and any macroscopic nodules in any organs detectable on imaging techniques should no longer be present. Imaging should include PET scanning. CR will also include unconfirmed complete responses defined as a residual lymph node mass > 1.5 cm in greatest transverse diameter that has regressed by > 75% in sum of the products of the greatest perpendicular diameters (SPD), or any residual lesions in organs that have decreased by > 75%, with a negative PET scan, negative bone marrow and CSF.

 

  1. Peripheral T cell lymphoma (PTCL).
    1. In first response (must have at least a partial response)
      1. PTCL, unspecified.
      2. Hepatosplenic gamma-delta T cell lymphoma
    2. Recurrent PTCL (must be treatment sensitive with at least a partial response). If patient has had a previous autologous transplant, the melphalan and fludarabine conditioning regimen must be utilized.

 

For these lymphomas a Complete Response (CR) is defined as the disappearance of all detectable clinical evidence of disease and disease-related symptoms present before therapy.  Post-treatment residual nodal mass of any size is permitted as long as it is PET negative and the disease is FDG avid. If the lymphoma is variably FDG-avid or PET negative, regression of nodal masses to normal size must be demonstrated by CT scan.  Spleen and liver must be normal in size with disappearances of nodules (assessed as described for nodal mass).  The bone marrow should be negative by morphology (or immunohistochemistry if morphology is indeterminate).

For these lymphomas, a partial response (PR) is defined as at least a 50% decrease in sum of the product of the perpendicular diameters (SPPD) of up to 6 of the largest dominant nodes or nodal masses (if FDG-avid, based on PET; if variably FDG-avid or PET negative based on CT scan). There should be no increase in the size of other lymph nodes. Splenic and hepatic nodules must regress by 50% in their SPPD or, for single nodules, in the greatest transverse diameter. There should be no measurable disease involving other organs. No new sites of disease. At sites where the FDG-PET scan was positive before therapy, the post-treatment PET is positive at one or more of the previously involved sites. Bone marrow may be positive or negative for disease.

(h)Chronic myelomonocytic leukemia.
 
(i) Atypical (BCR-ABL negative) chronic myelogenous leukemia
 
(j) Hodgkin lymphoma that has recurred or progressed after an autologous BMT.
 
(i) Newly diagnosed or recurrent disease initially refractory to intensive chemotherapy. A partial response or better must be achieved prior to transplantation. Please see (g) for definitions of response. Eligibility of newly diagnosed cases must be discussed with the study PI.
 
(ii) Disease that has recurred or progressed after an autologous BMT. Salvage chemotherapy must produce a partial response or better. Please see (g) for definitions of response. The melphalan and fludarabine conditioning-regimen must be used for these patients.
 
(k)Non-Hodgkin lymphoma (other than lymphoblasitc (f) or peripheral T cell lymphoma (g)).
 
(i) Newly diagnosed or recurrent disease initially refractory to intensive chemotherapy. A partial response or better must be achieved prior to transplantation. Please see (g) for definitions of response. Eligibility of newly diagnosed cases must be discussed with the study PI.
 
(ii) Disease that has recurred or progressed after an autologous BMT. Salvage chemotherapy must produce a partial response. Please see (g) for definitions of response. The melphalan and fludarabine conditioning-regimen must be used for these patients.

Exclusion Criteria

  1. Prior allogeneic HSCT.
  2. The patient is enrolled on a COG trial that uses criteria for unrelated donor HSCT, which conflict with our eligibility criteria.
  3. The patient is enrolled on a COG trial that utilizes unrelated donor HSCT and requires that patients be transplanted using an approach specified by the protocol that is in conflict with the approach specified in this protocol.
  4. Availability of a willing and suitable HLA identical related donor.
  5. Uncontrolled viral, bacterial, fungal or protozoal infection at the time of study enrollment.
  6. HIV infection.
  7. Serious psychiatric disease including schizophrenia, bipolar disorder and severe depression.
  8. Any patient with a known or suspected inherited predisposition to cancer should be discussed with the study team prior to screening for eligibility.
    • Patients with a known inherited or constitutional predisposition to transplant morbidities, including, but not limited to Fanconi Anemia, Dyskeratosis Congenita, Shwachman-Diamond Syndrome and Down Syndrome will be excluded.
    • Patients with known inherited or constitutional predisposition to non-hematologic cancers including, but not limited to Li-Fraumeni syndrome, BRCA1 and BRCA2 mutations will be excluded.
    • Patients with an inherited predisposition to leukemia or otherwise hematologic malignancies that have not been associated with predisposition to transplant morbidities or non-hematologic cancers will not be excluded.
  9. Patient with a secondary malignancy who would be otherwise eligible for study, but for whom remission from the primary disease cannot be conclusively confirmed or for whom the chance of relapse of the primary disease is significant.
  10. Incompletely treated active tuberculosis Infection.
  11. Pregnancy (positive serum b-HCG) or breastfeeding.
  12. Estimated GFR of < 50 mL/min/1.73m2.
  13. Cardiac ejection fraction < 50  (using M-Mode if assessment is done by ECHO).
  14. bilirubin > 2 × upper limit of normal or ALT > 4 × upper limit of normal or unresolved veno-occlusive disease.
  15. Pulmonary disease with FVC, FEV1 or DLCO parameters <45% predicted (corrected for hemoglobin) or requiring supplemental oxygen. Children who are developmentally unable to perform pulmonary function testing will be assessed solely on their need for supplemental oxygen.
  16. Karnofsky performance score or Lansky Play-Performance Scale score <80
  17. Presence of antibodies to a mismatched donor HLA antigen (please refer to Section 3.4.g protocol summary).